Process for the preparation of copolyesters

ABSTRACT

Copolyesters are prepared using cyclic esters or carbonates as monomers and a metallic salt of the formula Me 2+ X 2  as catalyst. Me 2+  represents Ca, Fe(II), Mg, Mn(II) or Zn, and X is an anion of an aminocarboxylic acid, hydroxycarboxylic acid or a halide. Monomer and catalyst are used in a monomer/catalyst ratio of greater than 100.

The invention relates to a process for the preparation of copolyestersusing cyclic esters as monomers and a metallic salt of the formulaMe²⁺X₂ as catalyst.

Biologically degradable plastics such as polylactides or copolyesters oflactic acid with other hydroxycarboxylic acids are used to an increasingextent for medical and pharmaceutical purposes, for example as matrixmaterials for pharmaceutical active ingredients, as medical suturematerials, as devices for setting bone fractures or as wound materials.

Amorphous polymers are generally preferred in the preparation of depotmedicaments, since they exhibit a homogeneous degradation behaviour inthe body and therefore ensure a uniform release of the activeingredient. Moreover, active ingredients can form deposits better inamorphous than in crystalline polymer regions.

Since homopolymers mostly have a semicrystalline structure, copolymersare preferred for the preparation of depot medicaments.

Gilding and Reed, Polymer 20 (1979) 1459, describe the preparation ofcopolyesters of glycolic and lactic acid using tin octoate as initiator.Tin octoate, however, allows only insufficient control of thepolymerization reaction. Initially, the glycolide predominantlyincorporated into the growing polymer chains due to the differentreactivities of the monomers. Only when this is largely used up does anoteworthy incorporation of the lactide take place. As a consequence,block copolymers are obtained which tend to form crystalline regions.Moreover, the use of tin salts and other heavy metal salts in thepreparation of polymers for medical purposes is problematical.

Kricheldorf et al., Makromol. Chem., Suppl. 12, 25-38 (1985) 25,investigate the copolymerization of glycolide with L,L-lactide and otherlactones. In addition to tin salts, FeCl₃, ZnCl₂, ZnO, ZnS and zinc dustinter alia are used as initiators. Monomer and initiator are used in aratio of 100:1. Here, too, only block copolymers were obtained whenFeCl₃, ZnCl₂ and ZnS were used. Only ZnO and zinc dust resulted inamorphous copolymers at temperatures of 150° C., but ZnO brings about aracemization of L-lactide and produces only relatively low molecularweights. After polymerization, zinc powder must be laboriously separatedoff in an additional purification step, and the molecular weights of thepolymers can scarcely be controlled.

Bero et al., Makromol. Chem. 194 (1993), 907, and Kasperczyk and Bero,Makromol. Chem. 194 (1993), 913, disclose the copolymerization ofL,L-lactide and E-caprolactone using inter alia ZnEtOiPr as initiatorand chlorobenzene as solvent. The use of non-toxic solvents orsolvent-free reactions are not described.

None of the processes known up to now allows the reproducible,controlled preparation of copolyesters with a random sequence. Moreover,the use of the named initiators is in some cases associated with seriousdisadvantages.

The object of the present invention is to provide a process which allowsthe reproducible preparation of copolyesters with a random sequenceunder controlled conditions.

This object was surprisingly achieved by polymerizing cyclic esters inthe presence of a metallic salt according to the formula Me²⁺X₂, inwhich Me²⁺ represents Mg, Ca, Fe(II), Mn(II) or Zn, and X is an anion ofan aminocarboxylic acid, hydroxycarboxylic acid or a halide, and inwhich monomer and catalyst are used in a monomer/catalyst ratio ofgreater than 100.

Preferred aminocarboxylic acids are aliphatic or aromatic, α- orω-aminocarboxylic acid such as 4-amino- and/or 4-(acetylamino)benzoicacid, saturated or unsaturated C₁-C₁₈ acylaminobenzoic acid,particularly preferably C₂-C₁₈ acylaminobenzoic acid with an even numberof C atoms, in particular C₄, C₆, C₁₆ or C₁₈ acylaminobenzoic acid. Alsopreferred are α- and ω-aminoalkanoic acids, particularly α- andω-amino-C₂-C₆-alkanoic acids or N-acyl, N-alkoxycarbonyl or oligopeptidederivatives thereof, acyl preferably having the meaning given above.Particularly suitable N-alkoxycarbonyl radicals are C₁-C₁₈, inparticular C₁-C₄ alkoxycarbonyl radicals, most preferred isethoxycarbonyl. Preferred oligopeptide derivatives are dipeptidederivatives, in particular dipeptide derivatives of the amino acidsglycine, alanine, sarcosine and proline.

Preferred hydroxycarboxylic acids are aliphatic or aromatic α- orω-hydroxycarboxylic acids such as glycolic acid, β-hydroxybutyric acid,β-hydroxyvaleric acid, lactic acid, mandelic acid, 4-hydroxybenzoicacid, salicylic acid and N-acetylsalicylic acid.

Preferred halides are chloride, bromide and iodide.

Me²⁺ preferably represents Fe(II), Mn(II) or Zn, quite particularlypreferably Zn.

X preferably represents lactate, mandelate, glycolate, bromide, iodide,particularly preferably lactate, bromide, quite particularly preferablylactate.

Particularly preferred catalysts are iron(II) lactate, manganeselactate, zinc lactate, zinc mandelate, zinc bromide and zinc iodide, inparticular zinc bromide, zinc lactate and iron(II) lactate.

Two or more different monomers are used to prepare copolymers,preferably structurally different monomers being used, i.e. monomerswhich differ not only by virtue of their stereochemistry.

Suitable as monomers are in particular cyclic esters andcyclocarbonates. Preferred cyclic esters are dilactones, such asglycolide and lactides, as well as lactones and esters according to theformulae

in which m=0 to 4, preferably 1 to 2 and quite particularly preferably2. The index n represents 2 to 12, preferably 2 to 6 and particularlypreferably 2 to 4, and R represents H, CH₃ or C₂H₅.

Preferred lactides are L,L-lactide and the racemate of L,L-lactide andD,D-lactide. L,L-lactide is often also called L-lactide.

Lactones are inner esters of the hydroxycarboxylic acids. Preferredlactones are β-butyrolactone, ε-caprolactone, p-dioxanone and (L- orD,L)-δ-valerolactone. Quite particularly preferred are ε-caprolactoneand p-dioxanone.

Preferred cyclocarbonates are compounds according to the formula

in which p=1 to 8, preferably 1 or 2. R¹ and R² independently of oneanother represent H, straight-chain C₁-C₆ alkyl or form, together withthe carbon atom to which they are bound, a 5- or 6-membered Spiro ring.

Two different cyclic esters, in particular two different lactones and/ordilactones, or cyclocarbonates or a mixture of at least one cyclic esterand at least one cyclocarbonate are preferably reacted with one another.

Mixtures of lactide and glycolide, lactide and ε-caprolactone as well aslactide and trimethylene carbonate are preferred. Lactide and glycolideare preferably used in a molar ratio of 1:1 to 9:1, lactide andε-caprolactone or lactide and trimethylene carbonate in a ratio of 9:1to 1:9, in particular 9:1 to 1:1.

The polymerization is carried out primarily as a bulk polymerization,i.e. in the melt in the absence of solvents. Small amounts of an inertliquid such as e.g. paraffin oil or a siloxane, for examplepolydimethylsiloxane, can be added in order to improve heat transfer.The process according to the invention is preferably carried out in theabsence of water.

The initiators can be used in the form of solutions in order tofacilitate dosage. A preferred solvent is diethyl ether. Furthermore, itwas found that, when ether solutions of the catalyst are used, polymerswith higher molecular weights can be obtained. This process variant isparticularly suitable when metal halides are used.

The polymerization temperature is preferably 40 to 250° C., particularlypreferably 60 to 200° C. and quite particularly preferably 60 to 180° C.Most preferred is a temperature range from 100 to 160° C. The optimumreaction temperature for the system in question depends on the monomersused and on the catalyst used. For example in the case of mixtures oflactide and ε-caprolactone, a reaction temperature in the range from 100to 150° C., in the case of mixtures of glycolide and lactide atemperature in the range from 130 to 160° C. and in the case of mixturesof cyclocarbonates and ε-caprolactone a temperature in the range from 60to 120° C. is preferred.

The reaction time depends on the reaction temperature and on thecomposition of the reaction mixture and is usually between 2 hours and 2weeks, preferably between 0.5 and 2 days.

Monomer and catalyst are preferably used in a monomer/catalyst molarratio of >100 to 15,000, particularly preferably 150 to 4000.

The process according to the invention can be carried out in thepresence of coinitiators. Suitable as coinitiators are in particularalcohols, preferably primary alcohols. The coinitiators are incorporatedas a terminal group into the polyester chain. Biologically activepolymers and oligomers can be obtained by using biologically activealcohols such as geraniol, menthol, hormones, e.g. stigmasterol,testosterone or cortisone, vitamins, e.g. α-tocopherol, andpharmaceutical active ingredients. Moreover, a control of the molecularweight of the polymers is possible via the ratio of monomer tocoinitiator.

The process according to the invention allows the controlled andreproducible preparation of copolyesters with an approximately randomsequence under mild conditions. For example, during the copolymerizationof glycolide and lactide (molar ratio of glycolide to lactide 1:1),copolyesters are obtained with glycolide block lengths of less than 5,in particular less than 4 glycolic acid units.

Previously, the preparation of random copolyesters required either hightemperatures which resulted in small molecular weights, or the use oftoxic initiators or initiators disadvantageous for other reasons. Theinitiators used according to the invention contain exclusively ionswhich are found in the human or animal body. They are fully resorbableand biocompatible. The process is therefore particularly suitable forthe preparation of biologically degradable, resorbable polyesters.

Biologically degradable polyesters are those which can be enzymaticallyor hydrolytically degraded at temperatures below ca. 50° C. to harmless,low-molecular compounds.

Resorbable polyesters are those which are degraded fully to non-toxiccompounds in the animal or human body.

On account of the largely random distribution of the monomer components,the polymers prepared using the process according to the invention arepractically completely amorphous and have no crystalline regions. Theyare characterized by a very uniform biological degradation and aresuitable in particular for the preparation of medicaments withcontrolled release of the active ingredient such as, e.g., depotmedicaments, as carriers and containers for cell cultures, for examplefor osteosynthesis, for the preparation of films, powders and foams forwound treatment, for example transparent dressings for burns.

For the preparation of depot medicaments, a polymer prepared accordingto the invention is loaded with the desired active ingredient, forexample by coprecipitating the dissolved or suspended active ingredientwith the polymer from a polymer solution, by co-freeze-drying a solutionof polymer and active ingredient or by kneading the active ingredientinto the polymer. Suitable as active ingredients are, for example,steroid hormones, peptide hormones, contraceptives, antidepressants andantitumour reagents.

The release behaviour of the active ingredients can be varied withinbroad ranges by varying the composition and the molecular weight of thepolymer.

High active ingredient/polymer ratios can be achieved on account of theamorphous character of the polymers. Moreover, the amorphous structureguarantees a uniform degradation behaviour and thus ensures even releaseof the active ingredient.

Catalysts are preferably used for the polymerization with a purity of atleast 97%, preferably 99% and particularly preferably >99%. Catalysts ofthis degree of purity can be obtained from commercial products bycustomary purification processes such as for example byrecrystallization. A high purity of catalysts and monomers favours theformation of polymers with high molecular weights.

Particularly pure zinc lactate can be obtained by suspending zinc oxideand/or zinc carbonate together with lactide, preferably L,L-lactide, inwater, then stirring the suspension until a clear solution is obtainedand subsequently isolating the product. For the isolation, the water isfor example evaporated until a cloudy solution forms, which is cooled.The precipitated product can be filtered off. The crude product can bepurified further by recrystallization from water. This process produceszinc lactate of high purity and one of the remarkable features of thisprocess is characterized by its simple handling.

Alternatively pure zinc lactate can be obtained by mixing ZnO,ethyl-L-lactate and water and heating the mixture until a clear solutionis obtained. The zinc lactate formed can be isolated by concentratingthe solution by removal of the solvent followed by cooling. Theprecipitated product is filtered off and can be purified further asdescribed above.

The metallic salts according to the invention have a high storabilityand resistance to oxidation. Zinc lactate can be stored for practicallyunlimited periods. Moreover, the salts of the amino- andhydroxycarboxylic acids in particular are characterized by a very lowhygroscopicity. The catalysts are therefore easy to handle and ensurehigh reproducibility of the process according to the invention.

The invention is explained in more detail below with reference toembodiments.

EXAMPLE 1 Preparation of Zinc Lactate from Ethyl Lactate

ZnO (25 mmol, ZnO purissimum, E. Merck Co., Darmstadt, FRG),ethyl-L-lactate (100 mmol, [α]²⁰ _(D)=10°, Aldrich Co., Milwaukee, Wis.,USA) and water (100 ml) were mixed and stirred under reflux for 3 hours.The clear solution was concentrated in vacuo to ca. 50% of its initialvolume and then cooled in an ice bath. The precipitated product was thenfiltered off, recrystallized twice from water (in each case 30 ml) anddried at 110° C. in vacuo over P₄O₁₀.

Yield: 36%.

[α]²⁰ _(D) −8.1°, c = 2.5 g/dl in H₂O. C₆H₁₀O₆Zn (243.52 g/mol) Calc.: C29.59 H 4.14 Found: C 29.36 H 4.14

EXAMPLE 2 Preparation of Zinc Lactate from L-Lactide

L-lactide (S grade, Boehringer Ingelheim KG, Ingelheim, FRG) wasrecrystallized twice from ethyl acetate and dried over P₄O₁₀. ZnO (60mmol, E. Merck Co., Darmstadt, FRG) and the dried L-lactide (80 mmol)were suspended in distilled water (150 ml) and stirred for 24 hours at20 to 22° C. The clear solution was concentrated until cloudingoccurred, then cooled in an ice bath, and the precipitated product wasfiltered off. The untreated product was recrystallized from water (50ml). Yield: 40%.

[α]²⁰ _(D) − 9.1°, c = 2.5 g/dl in H₂O C₆H₁₀O₆Zn (243.52 g/mol) Calc.: C29.59 H 4.14 Found: C 29.97 H 4.18

EXAMPLE 3 Preparation of zinc-L-mandelate

ZnCl₂ (25 mmol, purity 99.9%, Aldrich Co., Milwaukee, Wis., USA) wasdissolved in water (100 ml) and the solution was added dropwise withstirring to a solution of Li-L-mandelate (60 mmol, Aldrich Co.,Milwaukee, Wis., USA) in water (100 ml). The precipitated product wasfiltered off, washed with cold water (1° C.) and recrystallized fromwater. Yield after drying at 110° C. in vacuo: 61%.

[α]²⁰ _(D) + 92.5°, c = 0.1 g/dl in H₂O C₁₆H₁₄O₆Zn (367.7) Calc.: C52.27 H 3.84 Found: C 51.85 H 3.86

EXAMPLE 4 Preparation of iron(II)-L-lactate

A solution of Li-L-lactate (50 mmol, Sigma Chemicals, Munich, FRG) inoxygen-free methanol (50 ml) and a solution of FeCl₂ (25 mmol) (AldrichCo., Milwaukee, Wis., USA), also in oxygen-free methanol (50 ml), weremixed slowly with stirring, a white deposit forming. The deposit wasfiltered off, washed with cold methanol until chloride-free and dried invacuo at 60° C. Yield: 47%.

[α]²⁰ _(D) + 12.88°, c = 2.5 g/dl in H₂O C₆H₁₀O₆Fe (236.0) Calc.: C30.80 H 4.31 Found: C 30.86 H 4.45

EXAMPLE 5 Copolymerization of glycolide and L,L-lactide using zinclactate as catalyst

Recrystallized glycolide, L-lactide (Aldrich Co., Milwaukee, Wis., USA)and catalyst were weighed in the proportions given in Table 1 undernitrogen into a 50 ml Erlenmeyer flask with silanized glass walls. Thereaction vessel was closed with a glass stopper which was secured with asteel clip, and fully immersed in a temperature-controlled oil bathhaving a temperature of 150° C. After 48 hrs, the flask was removed fromthe oil bath, cooled, the reaction product was dissolved indichloromethane (50 ml) and precipitated by pouring this solution intocold methanol (700 ml). The isolated copolyester was dried in vacuo at50° C.

TABLE 1 ZnLac₂-catalysed bulk copolymerization of glycolide andL,L-lactide at 150° C. with a reaction time of 48 hours Composition^(b))lactide/ Molar ratio monomer^(a))/ Yield glycolide ηinh^(c))/ Ex.lactide/glycolide catalyst [%] [%] dl/g 5.1 9/1 1000/1 92 89/11 0.70 5.28/2 1000/1 87 79/21 0.43 5.3 7/3 1000/1 92 70/30 0.54 5.4 6/4 1000/1 9057/43 0.49 5.5 5/5 1000/1 89 48/52 0.70 ^(a))molar sum of both monomers^(b))determined by means of the ¹H-NMR spectra ^(c))measured at 25° C.with c = 2 g/l in CH₂Cl₂/trifluoroacetic acid (volume ratio 4:1)

The composition of the copolyesters was determined by means of their¹H-NMR spectra by computer-aided quantification of the signalintensities. The ¹H-NMR spectra were measured at 25° C. using a BrukerAC-100 or AM-360 FT spectrometer in 5 mm o.d. sample tubes.

The inherent viscosities were determined using an automatic Ubbelohdeviscometer (Viscoboy, Lauda) thermostatically controlled at 25° C.

Optical rotations were measured in a polarimeter (Perkin Elmer Md 421)at 25° C. in 10 cm-long vessels.

EXAMPLE 6 Copolymerization of glycolide and L,L-lactide using zinclactate as catalyst

Glycolide (0.5 mol) and L-lactide (0.5 mol) (both S-grade, BoehringerIngelheim KG, Ingelheim) were heated to 150° C. in a 250 ml three-neckedflask with silanized glass walls, equipped with a stirrer, in order toobtain a homogeneous melt of both monomers. The initiator was thenadded, the reaction vessel was closed with glass stoppers and securedwith steel clips. The stirrer was removed after the mixture had becometoo viscous to be stirred. The third flask neck was also closed with aglass stopper and secured with a steel clip. The flask was cooled afterthe reaction times given in Table 2, 10 g of the reaction product weredissolved in dichloromethane/trifluoroacetic acid (volume ratio 4:1),precipitated in cold methanol, and the product was filtered off. Theisolated copolyester was dried in vacuo at 40° C.

The average block lengths of the glycolide (L_(G)) and lactide (L_(L))units were then determined by means of their ¹³C-NMR spectra. To thisend, the intensities of the CO signals were measured and evaluatedaccording to the following equations:$L_{G} = {{\frac{I_{GG}}{I_{GL}} + 1} = {\frac{I_{GG}}{I_{LG}} + 1}}$$L_{L} = {{\frac{I_{LL}}{I_{GL}} + 1} = {\frac{I_{LL}}{I_{CL}} + 1}}$

I_(GG) and I_(LL) are the signal intensities of CO signals whichindicate the linkage of glycolide units with glycolide units and lactideunits with lactide units.

I_(GL) and I_(LG) are the intensities of the CO signals which indicateglycolide-lactide and lactide-glycolide linkages (diads).

The results are summarized in Table 2.

TABLE 2 ZnLac₂-catalysed bulk copolymerization of glycolide andL,L-lactide (molar ratio 1:1) at 150° C. Reaction Monomer^(a))/ timeYield ηinh^(b))/ Average block length^(c)) Ex. Catalyst [hr] [%] dl/gL_(G) L_(L) 6.1  500/1 24 93 0.55 3.0 3.1 6.2  500/1 48 91 0.47 2.7 2.86.3 1000/1 48 89 0.70 2.9 3.1 6.4 1000/1 72 95 0.62 2.7 2.7 6.5 4000/148 85 0.62 3.7 3.5 6.6 4000/1 72 93 0.43 3.8 3.5 ^(a))molar sum of bothmonomers ^(b))measured at 25° C. with c = 2 g/l inCH₂Cl₂/trifluoroacetic acid (volume ratio 4:1) ^(c))determined by meansof the ¹³C-NMR Spectra

EXAMPLE 7 Copolymerization of L,L-lactide and ε-caprolactone using zinclactate as catalyst

Inanalogy to Example 5, L,L-lactide and ε-caprolactone werecopolymerized in a molar ratio of 1:2 at 120° C. and 150° C. The resultsare summarized in Table 3.

TABLE 3 ZnLac₂-catalysed bulk copolymerization of L,L-lactide andε-caprolactone (molar ratio 1:2) Composition^(b)) lactide/ Monomer^(a))/Temp. Time Yield caprolactone ηinh^(c))/ Ex. Catalyst (° C.) [hrs] [%][%] dl/g 7.1 1000/1 120 48 67 60/40 0.61 7.2 1000/1 150 48 90 49/51 0.757.3 1000/1 120 96 88 51/49 0.99 7.4 1000/1 150 96 90 49/51 0.80 7.51000/1 120 192  96 50/50 0.96 ^(a))molar sum of both monomers^(b))determined by means of the ¹H-NMR spectra ^(c))measured at 25° C.with c = 2 g/l in CH₂Cl₂

EXAMPLE 8 Copolymerization of ε-caprolactone and trimethylene carbonateusing zinc lactate as catalyst

5.7 g (0.05 mol) ε-caprolactone (distilled twice over CaH₂) and 5.1 g(0.05 mol) trimethylene carbonate (Boehringer Ingelheim, recrystallizedfrom ethyl acetate and dried in vacuo over phorphorus pentoxide) wereweighed into a 100 ml Erlenmeyer flask silanized withdimethyldichlorosilane. The flask was closed with a glass stopper andimmersed in an oil bath temperature-controlled at 100° C. and 150° C.respectively. After the monomers had melted, 0.0353 g Zn(lac)₂ wereadded as initiator (monomer/initiator=1000). The flask was again closedand left in the oil bath for the times mentioned in Table 4. The productwas then dissolved in 100 ml dichloromethane, precipitated from ca. 1 lcold methanol and stored in the freezer for 30 minutes. After themethanol had been decanted off, the product was dried in vacuo at roomtemperature. The results are summarized in Table 4.

Inanalogy to Example 6, the average block lengths of the ε-caprolactoneunits (L_(C)) and trimethylene carbonate units (L_(T)) were determined.The following values were found: L_(C)=2; L_(T)=2.

TABLE 4 ZnLac₂-initiated bulk copolymerization of ε- caprolactone andtrimethylene carbonate (TMC) (1:1) Composition^(b)) Monomer^(a))/ Temp.Time Yield caprolactone/ ηinh^(c))/ Ex. Initiator [° C.] [hrs] [%] TMC[%] dl/g 8.1 1000/1 100  8 — — — 8.2 1000/1 100 24  2 — — 8.3 1000/1 10048 87 49/51 0.80 8.4 1000/1 150  8 97 51/49  0.815 8.5 1000/1 150 24 9748.5/51.5 1.01 8.6 1000/1 150 48 95 52/48 0.83 ^(a))molar sum of bothmonomers ^(b))determined by means of the ¹H-NMR spectra ^(c))measured at25° C. with c = 2 g/l in CH₂Cl₂

EXAMPLE 9 Copolymerization of β-D,L-butyrolactone and trimethylenecarbonate using zinc lactate as catalyst

4.3 g (0.05 mol) β-D,L-butyrolactone (Aldrich) and 5.1 g (0.05 mol)trimethylene carbonate (Boehringer Ingelheim, recrystallized from ethylacetate and dried in vacuo over phorphorus pentoxide) were weighed intoa 100 ml Erlenmeyer flask silanized with dimethyldichlorosilane. TheErlenmeyer flask was closed with a glass stopper and immersed in an oilbath temperature-controlled at 100° C. After the monomers had melted,0.0353 g of Zn(lac)₂ were added as initiator (monomer/initiator=1000).The flask was again closed and left in the temperature-controlled oilbath for 8 to 72 hours. The product was then dissolved in 100 mldichloromethane, precipitated from ca. 1 l cold methanol and stored inthe freezer for 30 minutes. After the solvent had been decanted off, theproduct was dried in vacuo at room temperature. The results aresummarized in Table 5.

TABLE 5 ZnLac₂-initiated copolymerization of β-D,L- butyrolactone andtrimethylene carbonate (TMC) (1:1) Composition^(b)) Monomer^(a))/ Temp.Time Yield butyrolactone/ ηinh^(c))/ Ex. Initiator [° C.] [hrs] [%] TMC[%] dl/g 9.1 1000/1 100  8  6 24/76 — 9.2 1000/1 100 24 32 32.5/67.50.19 9.3 1000/1 100 72 18 38/62 0.19 ^(a))molar sum of both monomers^(b))determined by means of the ¹H-NMR spectra ^(c))measured at 25° C.with c = 2 g/l in CH₂Cl₂

EXAMPLE 10 Copolymerization of L,L-lactide and trimethylene carbonateusing zinc lactate as catalyst

4.8 g (0.033 mol) L,L-lactide (Boehringer Ingelheim) and 6.8 g (0.066mol) trimethylene carbonate (Boehringer Ingelheim) were weighed into a100 ml Erlenmeyer flask silanized with dimethyldichlorosilane. Bothmonomers had been recrystallized beforehand from ethyl acetate and driedin vacuo over phosphorus pentoxide. The Erlenmeyer flask was closed witha glass stopper and immersed in an oil bath temperature-controlled at100° C. and 150° C. respectively. After the monomers had melted,Zn(lac)₂ was added as initiator. The quantity of initiator was measuredin such a way that the monomer/initiator ratios listed in Table 6 wereattained (0.0176 g Zn(lac)₂ produce e.g. a monomer/initiator ratio of2000). The flask was again closed and left in the temperature-controlledoil bath for 8 to 168 hours. The product was then dissolved in 100 mldichloromethane, precipitated from ca. 1 l cold methanol and dried invacuo at 40° C. The results are summarized in Table 6.

Analogously to Example 6, the average block lengths of the L-lactideunits (L_(L)) and trimethylene carbonate units (L_(T)) were determined.The following values were found: L_(L)=1.8; L_(T)=2.7.

TABLE 6 Znlac₂-initiated bulk copolymerization of L,L-lactide andtrimethylene carbonate (TMC) (1:2) Composition^(b)) Monomer^(a))/ Temp.Time Yield lactide/TMC ηinh^(c))/ Ex. Initiator [° C.] [hrs] [%] [%]dl/g 10.1 500/1 100 24 19 67.5/32.5 0.26 10.2 500/1 100 48 71 57/43 0.3210.3 500/1 100 96 85 44/56  0.375 10.4 2000/1  100 72  8 67.5/32.5 0.1510.5 2000/1  100 96 24 57.5/42.5 0.24 10.6 2000/1  100 168  66 65/350.33 10.7 500/1 150  8 91 48.4/51.6 0.25 10.8 500/1 150 24 91 43.7/56.30.36 10.9 2000/1  150 24 90 51/49 0.38 10.10 2000/1  150 48 93 50.5/49.50.27 ^(a))molar sum of both monomers ^(b))determined by means of the¹H-NMR spectra ^(c))measured at 25° C. with c = 2 g/l in CH₂Cl₂

EXAMPLE 11 Copolymerization of glycolide and L,L-lactide using zinclactate as catalyst and diethylene glycol monobutyl ether as coinitiator

129.6 g (0.9 mol) L,L-lactide (degree of purity S, Boehringer Ingelheim,Ingelheim, FRG) and 11.6 g (0.1 mol) glycolide (degree of purity S,Boehringer Ingelheim, Ingelheim, FRG) were weighed into a 250 mlthree-necked flask silanized with dimethyldichlorosilane. Both monomershad been dried beforehand for 24 hours over phosphorus pentoxide invacuo in a desiccator. The three-necked flask was provided with a glassstirrer and a jacket, the other necks were closed with glass stoppersand secured with steel springs.

The flask was then immersed in an oil bath temperature-controlled at130° C. After the monomers had been melted with stirring, the flask wasopened and, with further stirring, 0.707 g zinc lactate were added ascatalyst (monomer/catalyst=500), and 4 ml of a 1 M solution ofdiethylene glycol monobutyl ether in dry dioxane were added ascoinitiator (monomer/coinitiator=250). The mixture was again left in theoil bath. The glass stirrer was removed after the resulting copolymerhad reached a viscosity which made further stirring impossible. Theopening was likewise closed with a glass stopper and the reaction wascontinued. After 8 days the flask was removed from the oil bath andcooled.

The working-up of the polymerization mixture was carried out asdescribed in Example 5. The analysis of the copolymer gave the followingresults: η_(inh)=0.49 dl/g; L_(L)=2; L_(G)=10; T_(g)=52° C. (determinedby DSC measurement).

EXAMPLE 12 Polymerization of L-lactide using zinc lactate as catalystand various biologically active alcohols as coinitiators

Inanalogy to Example 11, L-lactide was polymerized at 150° C. using zinclactate as catalyst. The biologically active alcohols listed in Table 7were added as coinitiators. The low viscosities and the ¹H-NMR spectrashow that vitamins and hormones are integrated into the polymer asterminal ester groups.

TABLE 7 Bulk polymerization of L-lactide^(a)) at 150° C. using ZnLac₂^(b)) as catalyst and various alcohols as coinitiators Calculated Degreeof Monomer/ ηinh^(c)) degree of polymer- Benzyl Yield _-/ polymer-ization^(e)) Ex. Coinitiator alcohol [%] dl/g ization^(d)) ¹H-NMR 12.1Testosterone 10 55 0.09 19 42 12.2 Tocopherol 10 51 0.12 19 31 12.3Stigmasterol 10 48 0.09 19 43 12.4 Testosterone 25 83 0.17 48 75 12.5Tocopherol 25 80 0.22 48 60 12.6 Stigmasterol 25 79 0.18 48 80^(a))Recrystallized once from ethyl acetate ^(b))monomer/catalyst ratio4000:1 ^(c))measured at 20° C. with c = 2 g/l in CH₂Cl₂ ^(d))calculatedas degree of polymerization = monomer/coinitiator molar ratio, assuminga 95% conversion according to the equation: Degree of polymerization =mol monomer/mol coinitiator · % conversion/100 ^(e))experimental valuesof ¹H-NMR terminal group analysis

EXAMPLE 13 Copolymerization of glycolide and L,L-lactide using zinclactate as catalyst

Inanalogy to Example 5, a mixture of glycolide (degree of purity S,Boehringer Ingelheim, Ingelheim, FRG) and L,L-lactide (degree. of purityS, Boehringer Ingelheim, Ingelheim, FRG) was polymerized at 150° C.using zinc lactate as catalyst. In each case 0.4 mol of the monomers wasused (molar ratio 1:1). Reaction conditions and results are summarizedin Table 8.

TABLE 8 ZnLac₂-initiated bulk copolymerization of glycolide andL,L-lactide (molar ratio 1:1) at 150° C.) Monomer^(a))/ Time Yieldηinh^(b))/ Average block length^(c)) Ex. Catalyst [hr] [%] dl/g L_(G)L_(L) 13.1  500/1 24 93 0.55 3.0 3.1 13.2  500/1 48 91 0.47 2.7 2.8 13.31000/1 48 89 0.70 2.9 3.1 13.4 1000/1 72 95 0.62 2.7 2.7 13.5 4000/1 4885 0.62 3.7 3.5 13.6 4000/1 72 93 0.43 3.8 3.5 ^(a))molar sum of bothmonomers ^(b))measured at 25° C. with c = 2 g/l inCH₂Cl₂/trifluoroacetic acid (volume ratio 4:1) ^(c))determinedanalogously to Example 6 by means of the ¹³C-NMR spectra

EXAMPLE 14 Copolymerization of glycolide and L,L-lactide using zincbromide as catalyst

72 g (0.5 mol) L,L-lactide (degree of purity S, Boehringer Ingelheim,Ingelheim, FRG) and 58 g (0.5 mol) glycolide (degree of purity S,Boehringer Ingelheim, Ingelheim, FRG) were weighed into a 250 mlthree-necked flask silanized with dimethyldichlorosilane. Both monomershad been dried beforehand for 24 hours over phosphorus pentoxide invacuo in a desiccator. The three-necked flask was provided with a glassstirrer and a jacket, the other necks were closed with glass stoppersand secured with steel springs. The flask was then immersed in an oilbath temperature-controlled at 150° C. After the monomers had beenmelted with stirring, the flask was opened and, with further stirring, 2ml of a 1 M ZnBr₂ solution in dry diethyl ether were added as catalyst(monomer/catalyst=500), and 4 ml of a 1 M solution of diethylene glycolmonobutyl ether in dry dioxane were added as coinitiator(monomer/coinitiator=250). The mixture was again left in the oil bath.The glass stirrer was removed after the resulting copolymer had reacheda viscosity which made further stirring impossible. The opening waslikewise closed with a glass stopper and the reaction was continued.After 96 hours the flask was removed from the oil bath and cooled. Theworking-up of the polymerization mixture was carried out as described inExample 5. The analysis of the copolymer gave the following results:η_(inh)=0.4 dl/g; L_(L)=2.3; L_(G)=2.2; T_(g)=42° C.

EXAMPLE 15 Copolymerization of L-lactide and glycolide usingmanganese(II) salts as initiators

Glycolide (12.5 mmol, recrystallized 1× from ethyl acetate), L-lactide(37.5 mmol, recrystallized 1× from ethyl acetate) and Mn(II) salt (0.1mol) were weighed into a 50 ml Erlenmeyer flask with silanized glasswalls. The flask was closed with a glass stopper and immersed in an oilbath thermostatically controlled at 150° C. After the monomers hadmelted, they were tossed for ca. 5 minutes in the oil bath in order toachieve thorough mixing. The flask was then left in the oil bath for 2to 3 days and then the reaction product was dissolved in 50 mldichloromethane, precipitated in 600 ml cold methanol and dried in vacuoat 40° C. The results for different Mn(II) salts are summarized in Table9.

TABLE 9 Bulk copolymerization of L-lactide and glycolide (3:1) at 150°C. Monomer/ Time Yield^(a)) ηinh^(b)) Ex. Initiator Catalyst [hrs] [%][dl/g] 15.1 MnCl₂  500/1 48 40 0.23 15.2  500/1 72 49 0.22 15.3 2000/148 37 0.22 15.4 2000/1 72 42 0.22 15.5 MnBr₂  500/1 48 82 0.32 15.6 500/1 72 89 0.24 15.7 2000/1 48 55 0.24 15.8 2000/1 72 54 0.20 15.9MnI₂  500/1 48 83 0.25 15.10  500/1 72 85 0.24 15.11 2000/1 48 11 —15.12 2000/1 72 26 0.16 15.13 Mn acetate  500/1 48 84 0.25 15.14  500/172 89 0.25 15.15 2000/1 48 55 0.24 15.16 2000/1 72 67 0.21 15.17^(c)) Mnlactate  500/1 48 81 0.29 15.18  500/1 72 90 0.30 15.19 2000/1 48 430.27 15.20 2000/1 72 48 0.22 ^(a))after precipitation in methanol^(b))measured at 25° C. with c = 2 g/l in CH₂Cl₂ (1:4) ^(c))ratio ofL-lactide/glycolide = 3.1:1 (determined by ¹H-NMR spectroscopy)

EXAMPLE 16 Copolymerization of L-lactide and glycolide using iron(II)salts as initiators

Glycolide (12.5 mmol, recrystallized 1× from ethyl acetate), L-lactide(37.5 mmol, recrystallized 1× from ethyl acetate) and Fe(II) lactate orFeCl₂ were weighed into a 50 ml Erlenmeyer flask with silanized glasswalls, the flask was closed with a glass stopper and immersed in an oilbath thermostatically controlled at 150° C. After the monomers hadmelted, the flask was tossed in the oil bath for ca. 5 minutes in orderto achieve thorough mixing. After a reaction time of 2 to 4 days, thereaction product was dissolved in 50 ml dichloromethane, precipitated in600 ml cold methanol and dried in vacuo at 40° C. The results aresummarized in Table 10.

TABLE 10 Bulk copolymerization of L-lactide and glycolide (3:1) at 150°C. Monomer/ Time Yield^(a)) ηinh^(b)) Ex. Initiator Catalyst [hrs] [%][dl/g] 16.1 Fe lactate  500/1 48 74 0.27 16.2  500/1 72 77 0.3316.3^(c)) 2000/1 48 71 0.33 16.4 2000/1 72 74 0.34 16.5 FeCl₂  500/1 4877 0.31 16.6  500/1 72 82 0.31 16.7 2000/1 48 65 0.23 16.8 2000/1 72 720.28 ^(a))after precipitation in methanol ^(b))measured at 25° C. with c= 2 g/1 in TFA/CH₂Cl₂ (1:4) ^(c))ratio of L-lactide/glycolide 2.9:1(determined by ¹H-NMR spectroscopy)

EXAMPLE 17 Copolymerization of L-lactide and caprolactone using zincsalts as initiators

Caprolactone (33.3 mmol, 1× distilled), L-lactide (16.7 mmol,recrystallized 1× from ethyl acetate) and Zn(II) salicylate or Zn(II)prolinate (zinc salt of the amino acid proline) were weighed into a 50ml Erlenmeyer flask with silanized glass walls, the flask was closedwith a glass stopper and immersed in an oil bath thermostaticallycontrolled at 1500C. After the lactide had melted, the flask was tossedin the oil bath for ca. 5 minutes in order to achieve thorough mixing.After a reaction time of 2 to 4 days, the reaction product was dissolvedin 50 ml dichloromethane, precipitated in 600 ml cold methanol and driedin vacuo at 40° C. The results are shown in Table 11.

TABLE 11 Bulk copolymerization of L-lactide and caprolactone (1:2) at150° C. Monomer/ Time Yield^(a)) ηinh^(b)) Ex. Initiator Catalyst [hrs][%] [dl/g] 17.1 Zn salicylate  500/1 48 88 0.38 17.2  500/1 96 58 0.4417.3 2000/1 48 86 0.29 17.4^(c)) 2000/1 96 91 0.42 17.5 Zn prolinate 500/1 48 64 0.24 17.6  500/1 96 82 0.29 17.7 2000/1 48 68 0.25 17.82000/1 96 76 0.37 ^(a))after precipitation in methanol ^(b))measured at25° C. with c = 2 g/l in CH₂Cl₂ ^(c))ratio of E-oxycaproyl/lactyl units1.1:1; length of ε-oxycaproyl blocks: L_(c) = 3.24

EXAMPLE 18 Copolymerization of L-lactide and caprolactone usingmanganese(II) salts as initiators

Inanalogy to Example 17, a mixture of caprolactone (33.3 mmol) andL-lactide (16.7 mmol) was copolymerized using MnBr₂ or Mn lactate at150° C. The reaction conditions and results are summarized in Table 12.

TABLE 12 Bulk copolymerization of L-lactide and caprolactone (1:2) at150° C. Monomer/ Time Yield^(a)) ηinh^(b)) Ex. Initiator Catalyst [hrs][%] [dl/g] 18.1 MnBr₂  500/1 48 66 0.30 18.2  500/1 96 72 0.33 18.32000/1 48 16 0.32 18.4 2000/1 96 34 0.32 18.5 Mn lactate  500/1 48 770.27 18.6  500/1 96 79 0.32 18.7 2000/1 48 23 0.33 18.8 2000/1 96 480.39 ^(a))after precipitation in methanol ^(b))measured at 25° C. with c= 2 g/l in CH₂Cl₂

What is claimed is:
 1. A process for the preparation of copolyestersusing cyclic esters or cyclocarbonates or a mixture of at least onecyclic ester and at least one cyclocarbonate as monomers and a metallicsalt of the formula Me²⁺X₂ as catalyst, wherein Me²⁺ represents Ca,Fe(II), Mg, Mn(II) or Zn, and X is an anion of an aminocarboxylic acid,hydroxycarboxylic acid, bromide or iodide, that monomer and catalyst areused in a monomer/catalyst molar ratio of greater than 100, and themonomers are structurally different.
 2. A process according to claim 1,wherein Me²⁺ represents Fe(II), Mn(II) or Zn.
 3. A process according toclaim 1, wherein said aminocarboxylic acid is 4-amino- or4-(acetylamino)benzoic acid, a saturated or unsaturated C₁-C₁₈acylaminobenzoic acid, an α- and ω-amino-C₂-C₆-alkanoic acid, or aN-acyl, N-alkoxycarbonyl or oligopeptide derivative thereof.
 4. Aprocess according to claim 1, wherein X is mandelate, glycolate, iodide,bromide or lactate.
 5. A process according to claim 1, wherein ironlactate, manganese lactate or zinc lactate is used as catalyst.
 6. Aprocess according to claim 1, wherein at least two different cyclicesters or cyclocarbonates or a mixture of at least one cyclic ester andat least one cyclocarbonate is used as monomers.
 7. A process accordingto claim 6, wherein a glycolide, a lactide, a lactone of the formula

a dioxanone of the formula

and/or an ester of the formula

is used as cyclic ester, in which n=1-12 and R represents H, CH₃ andC₂H₅.
 8. A process according to claim 6, wherein a cyclocarbonate of theformula

is used as monomer, in which p=1-8, and R¹ and R² independently of oneanother represent H or straight-chain C₁-C₁₆ alkyl or, together with thecarbon atom to which they are bound, form a 5- or 6-membered spiro ring.9. A process according to claim 6, wherein β-butyrolactone,ε-caprolactone, p-dioxanone and/or (L- or D, L)-δ-valerolactone is/areused as lactone.
 10. A process according to claim 1, wherein thepolymerization is carried out in the melt in the absence of solvents.11. A process according to claim 1, wherein the polymerization iscarried out at a temperature of 40 to 250° C.
 12. A process according toclaim 1, wherein monomer and catalyst are used in a monomer/catalystmolar ratio of 150 to 15,000.
 13. A process according to claim 1,wherein, in addition, an alcohol is used as coinitiator.
 14. A processaccording to claim 13, wherein a vitamin, hormone and/or apharmaceutical active ingredient is/are used as coinitiator.
 15. Aprocess for the preparation of a medicament with controlled release ofan active ingredient, comprising loading the polymer prepared accordingto claim 1 with a pharmaceutical active ingredient.
 16. A processaccording to claim 15, wherein said active ingredient is dissolved orsuspended in a polymer solution and then coprecipitated jointly with thepolymer.
 17. A copolyester produced by the process of claim
 1. 18. Amedicament providing controlled release of an active ingredient, themedicament comprising an active ingredient incorporated in the copolymerproduced by the process of claim
 1. 19. A process according to claim 1,wherein said hydroxycarboxylic acid is glycolic acid, β-hydroxybutyricacid, β-hydroxyvaleric acid, lactic acid, mandelic acid,4-hydroxybenzoic acid, salicylic acid, or N-acetylsalicylic acid.
 20. Aprocess according to claim 1, wherein X is bromide or iodide.
 21. Aprocess according to claim 15, wherein said active ingredient and saidpolymer are dissolved in a solvent followed by freeze drying of thissolution.
 22. A process according to claim 15 wherein said activeingredient is kneaded into said polymer.